JP3499246B2 - Method for producing camptothecin derivatives - Google Patents

Abstract

PCT No. PCT/US96/17574 Sec. 371 Date May 14, 1998 Sec. 102(e) Date May 14, 1998 PCT Filed Nov. 1, 1996 PCT Pub. No. WO97/16454 PCT Pub. Date May 9, 1997The present invention relates to a process for preparing camptothecin and camptothecin analogs of Formula (I) from compounds of Formula (II) and to novel intermediates useful in their preparation, wherein R1 to R6 represent various substituents.

Description

FIELD OF THE INVENTION The present invention relates to methods for making camptothecin and camptothecin analogs using compounds that are useful as intermediates, and methods for making the intermediates.

BACKGROUND OF THE INVENTION Camptothecin is a naturally occurring compound found in Camptotheca acuminata. Camptothecin and camptothecin analogs have anti-leukemic and anti-tumor properties.

Camptothecin and camptothecin analogs can be found in Wall
U.S. Pat. No. 4,89, issued Jan. 16, 1990 to et al.
4,456, U.S. Pat. No. 4,399,282 issued Aug. 16, 1983 to Miyasaka et al., Miyasaka et a
U.S. Pat. No. 4,399,276 issued Aug. 16, 1983 to L.
No. 4,943,579, issued July 24, 1990 to Vishnuvajjala et al., SmithKline Be.
European Patent Application No. 0,321,122, A2 filed by cham Corporation and published on June 21, 1989, Miya
US Patent No. issued on September 25, 1984 to saka et al.
No. 4,473,692, filed by Kabushiki Kaisha Yakult Honsh, published European patent application 0,325,247, A2 on July 26, 1989, Takeda Chemical Indust.
European Patent Application No. 0,556,585, A2, filed Aug. 25, 1993, filed by ries, Wall et al. 199.
U.S. Pat. No. 4,981,968 issued Jan. 1, 1st, Wall et al. U.S. Pat. No. 5,049,668 issued Sep. 17, 1991, Comins et al. Nov. 1992 Ten
U.S. Pat.No. 5,162,532, Wall et
U.S. Pat. No. 5,180,72 issued Jan. 19, 1993 to al.
No. 2, and Glaxo Inc. filed, 1993
It can be synthesized using the method described in European Patent Application No. 0.540,099, A1 published May 5, 2015.

Conventional methods used to make camptothecin and camptothecin analogs use resolution and chiral-assisted methods to obtain enantiomerically enriched intermediates. The problem with these methods is that half of the racemic material must be discarded in the resolution, and the chiral auxiliary method requires the stereoselective setting of the chiral center using the stoichiometric amount of chiral subunits. Is.

Methods using catalytic asymmetric induction methods are described in US patent application Ser. No. 08 / 237,081 and Fang et al., Journal.
of Organic Chemistry, 59 (21), 6142-6143 (1994). One potential problem with such conventional methods is that some of the chirally specific intermediates are themselves cytotoxic. In addition, the final stage of the synthesis described in U.S. patent application Ser.No. 08 / 237,081 requires the use of a palladium catalyst, which is subsequently removed from the final drug substance by repeated recrystallizations. There must be. Due to the potential cytotoxicity of camptothecin and some of its analogs, strict protective measures must be taken at all later stages of manufacturing to protect the personnel and environment involved in production. Such protection measures increase the complexity and cost of manufacturing and handling camptothecin and its analogs.

The object of the present invention is a process for the production of camptothecin and its analogues, characterized in that the chirality at position 20 is not introduced until the penultimate production stage. This reduces the risk of accidental pollution of the environment and injury to production workers, and thus the handling and storage of highly bioactive materials, thus reducing the need for strict protective measures.

SUMMARY OF THE INVENTION The present invention provides a process for preparing a compound of formula (I), and pharmaceutically acceptable salts thereof, comprising oxidizing a compound of formula (II).

[In the above formula, R ₁ and R ₂ may be the same or different and are independently hydrogen, lower alkyl, (C _3-7 ) cycloalkyl, (C _3-7 ) cycloalkyl lower alkyl, lower alkenyl, hydroxy lower alkyl or alkoxyalkyl at either, or a _{(-CH 2 NR 7 R 8)} , where, i) R ₇ and R ₈ may be the same or different, independently hydrogen, lower _{alkyl, (C 3 to 7) cycloalkyl, (C 3 to 7)} cycloalkyl lower alkyl,
Lower alkenyl, hydroxy lower alkyl, or lower alkoxy lower alkyl, or ii) R ₇ is hydrogen, lower alkyl, (C _3-7 ) cycloalkyl, (C _3-7 ) cycloalkyl lower alkyl,
Lower alkenyl, hydroxy lower alkyl, or lower alkoxy lower alkyl, and R ₈ is —COR ₉ (in the above formula, R ₉ is hydrogen, lower alkyl, perhalo lower alkyl,
(C _3-7 ) cycloalkyl, (C _3-7 ) cycloalkyl lower alkyl, lower alkenyl, hydroxy lower alkyl, lower alkoxy, lower alkoxy lower alkyl) or iii) R ₇ is hydrogen or Is lower alkyl, R ₈ is
Diphenyl-methyl or (CH ₂ ) _t Ar (wherein t is 0-5, Ar is optionally one or more substituents selected from hydroxy, methyl, halogen, and amino) Phenyl, furyl, pyridyl, N-methylpyrrolyl, imidazolyl) substituted with or iv) R ₇ and R ₈ together with the nitrogen to which they are attached,
Expression (IA) (In the above formula, Y is O, S, SO, SO ₂ , CH ₂ , or NR ₁₀ , wherein R ₁₀ is hydrogen, lower alkyl, perhalo lower alkyl, aryl, lower alkyl, lower alkoxy. , Halogen, nitro, amino, lower alkylamino,
It is aryl substituted with one or more substituents selected from perhalo-lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl group, or -COR ₁₁ (in the above formula, R ₁₁ is hydrogen, lower alkyl). , Perhalo lower alkyl, lower alkoxy, aryl, lower alkyl, perhalo lower alkyl, hydroxy lower alkyl,
Is an aryl substituted with one or more substituents selected from lower alkoxy lower alkyl groups), or R ₃ and R ₄ are independently hydrogen, lower alkyl, (C
_3-7) cycloalkyl, (C _3-7) cycloalkyl lower alkyl, selected from lower alkenyl, hydroxy lower alkyl, or alkoxyalkyl, or R ₃ and R ₄ together, formula (IB) (Where n is an integer 1 or 2 in the above formula) saturated 5
Or forming a heterocyclic group of 6 atoms, or R ₃ is —OCONR ₁₂ R ₁₃ (wherein R ₁₂ and R ₁₃ may be the same or different and are independently hydrogen, Selected from substituted or unsubstituted alkyl groups having 1 to 4 carbon atoms, or substituted or unsubstituted carbocyclic or heterocyclic groups, provided that R ₁₂ and R
_{When 13} are both substituted or unsubstituted alkyl groups, they are combined with the nitrogen atom to which they are attached to -O-, -S-, and / or> N.
-R ₁₄ (wherein, R ₁₄ is hydrogen, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, or a substituted or unsubstituted phenyl group) to form a heterocycle which may be inserted. R ₅ is hydrogen, or alkyl, especially methyl, and R ₆ is hydrogen, or alkyl, especially hydrogen.] The present invention provides compounds of formula (II) with dihydroxy. Also provided is a method of making a compound of formula (I) comprising oxidization followed by oxidation to produce a compound of formula (I).

In addition to the method for producing the compound of formula (I) from the compound of formula (II), another embodiment of the present invention is to form a compound of formula (II) and a compound of formula (I) and (II) Various useful intermediates are included. Other aspects and advantages of this invention will be apparent upon reviewing the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION The term "lower alkyl" as used herein is a linear or branched alkyl group having 1 to 8, preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl. , N-butyl, tert-butyl, hexyl, and octyl. This definition also applies to lower alkyl groups such as lower alkoxy, lower alkylthio, and di (lower alkyl) amino groups. Thus, examples of lower alkoxy groups are methoxy, ethoxy, propoxy, sec-butoxy, and iso-hexoxy, examples of lower alkylthio groups are methylthio, ethylthio, tert-butylthio, and hexylthio,
Examples of di (lower alkyl) amino groups are dimethylamino,
Diethylamino, diisopropylamino, di (n-butyl) amino, and dipentylamino.

The terms "halo" and "halogen" as used herein refer to a substituent that may be fluoro, chloro, bromo, or iodo. The term [triflate] as used herein refers to trifluoromethanesulfonate. As used herein, the name "C" is
Means Celsius. The term "ambient temperature" as used herein means about 20 ° C to about 30 ° C.

The compounds of the present invention have the enantiomeric configuration, or "R"
And can have one or more asymmetric carbon atoms forming an "S" configuration. The present invention includes all enantiomeric forms and any combination of these forms. For simplicity, when a particular configuration is not represented by a structural formula, it should be understood to represent both enantiomeric forms and mixtures thereof. Unless otherwise noted, the nomenclature "(R)" and "(S)" refer to essentially pure R and S enantiomers, respectively, as the case may be.

Other forms of compounds such as solvates, hydrates, various polymorphs and the like are also included in the invention.

Acceptable salts include salts of inorganic acids and bases, such as hydrochlorides, sulfates, phosphates, diphosphates, hydrobromides, and nitrates, or salts with organic acids, such as acetates. Malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, pamoate, salicylate, oxalate and stearate Examples include, but are not limited to: For other examples of acceptable salts, see “pharmaceutical Salts” J. Phar.
See m.Sic., 66 (1), 1 (1977).

In one aspect of the invention, formula (III) A method for producing a compound of formula (II) A compound of claim 1 is dihydroxylated using a catalytic asymmetric dihydroxylation reaction. Typically, this reaction involves osmium catalysts (eg potassium osmium (VI) dihydrate, osmium chloride hydrate, or osmium tetroxide), chiral tertiary amine catalysts (eg hydroquinone 1,4- Derivatives of cinchona alkaloids such as phthalazine diyl diethers), oxidizing reagents (eg potassium ferri (III) cyanide, hydrogen peroxide, N-methylmorphine N-oxide, or electricity), and primary amides A polar protic solvent (eg t-butanol, i-propanol, etc.) under basic conditions (eg calcium carbonate) in the presence of (eg methanesulfonamide).
Alternatively, it can be carried out in an aqueous mixture containing n-propanol). The reaction is carried out at a temperature of about 0 ° C. to about 30 ° C.
It can be done for about 48 hours. Acceptable variations on these conditions are found in the literature for related catalytic asymmetric dihydroxylation reactions, such as KBSharpless et al., J. Or.
g. Chem., 58, 3785-3786 (1993).

Alternatively, the compound of formula II is oxidized to the compound of formula III in an achiral dihydroxylation reaction to give the racemic cis-diol, which is then enzymatically resolved to give the enantiomer concentration of formula III Yields high compounds. Achiral dihydroxylation is based on Larock, Comprehensive Organic Transfo
rmations, 493-496 (1989).
The split reaction is pancreatic lipase, Pseudomonas fluorensce
ns lipase, C. Cylindracea lipase, Chromobacterium
It can be performed in the presence of an acylating enzyme such as viscosum lipase and Aspergillus niger lipase in the presence of an acylating agent such as vinyl acetate at a temperature between about 0 ° C. and ambient temperature for about 2 to about 48 hours. it can. A modification to these conditions is A. Klibanov, Asymmetric Transformation Catalysis Catalyzed by Enzymes in Organic Solvents.
zed by Enzymes in Organic Solvents), Acc.Chem.Re
s., 23, 114-120 (1990).

The compound of formula (II) has the formula (IV) Where X is triflate or halo, especially chloro-, bromo-, and iodo-.
It can be prepared by cyclization of the compound of

The compound of formula (IV) can be cyclized by an intramolecular Heck reaction. The reaction is carried out with a palladium catalyst (eg,
In the presence of palladium (II) acetate, under basic conditions a polar aprotic solvent (eg acetonitrile or
N, N-dimethylformamide) or a polar protic solvent (eg, n-propanol, i-propanol, or t-butanol). When a polar aprotic solvent is used, mention may be made of phase transfer catalysts such as halogenated tetraalkylammonium salts (eg tetrabutylammonium chloride, tetrabutylammonium bromide, or tetrabutylammonium iodide). Preference is also given to palladium-catalyzed ligands such as triphenylphosphine, tri-o-tolylphosphine, tri-m-tolylphosphine, or tri-p-tolylphosphine. The reaction can be carried out in an inert atmosphere such as under nitrogen or argon gas in a suitable reaction vessel equipped with a mechanical stirrer and a water cooled condenser. The reaction mixture is about 50 ° to about 11 °
It can be heated at a temperature of 0 ° C. for about 1 to about 48 hours. Changes in these conditions can be found in the literature on Heck reactions, such as R. Grigg et al., Tetrahedron, 46, 4003-4008 (1990).
It is described in.

The compound of formula (IV) can be produced by condensing the compound of formula (V) with the compound of formula (VI).

[Wherein X is triflate or halo, especially chloro-, bromo-, and iodo-, and Z is chloro-, bromo-.
And iodo-, or a suitable leaving group such as OR ₁₅ where R ₁₅ is triflate, mesylate or tosylate, or especially H. ] When Z is hydroxy, the condensation reaction is carried out with a trialkyl- or triarylphosphine, such as triphenylphosphine, in an aprotic solvent, such as methylene chloride, with a dialkylazodicarboxylate, such as diethylazodicarboxylate. In the presence of
To about 50 ° C. for about 0.5 to 4 hours. Other variations on the above conditions will be apparent from the literature on the Mitsunobu reaction, such as O. Mitsunobu, Synthesis, 1, (1981).

When Z is halo, triflate, mesylate, or tosylate, the condensation reaction is a polar aprotic solvent such as acetonitrile or N, N-dimethylformamide, or a polar solvent such as i-propanol or t-butanol. From about 25 ° to about 1000 in the presence of a base such as potassium t-butoxide in a protic solvent.
Performing at a temperature of ° C for about 1 to 24 hours gives the compound of formula (IV). Changes to the above conditions are described in Comins et al. 1993.
No. 5,254,690, issued Oct. 19, 2014, the contents of which are incorporated herein by reference.

Compounds of formula (VI) can be prepared from compounds of formula (VII).

(Wherein R ₁₆ is alkyl, especially methyl.) The dealkylation reaction is carried out in a polar aprotic solvent such as acetonitrile in the presence of a suitable dealkylating reagent such as a trialkylsilyl iodide. Under about 0 ℃ ~ 10
It can be carried out at a temperature of 0 ° C. for about 1 to 12 hours. Trialkylsilyl iodide is a trialkylsilyl halide,
For example, it can be generated in situ by combining trimethylsilyl chloride with an alkali metal iodide, such as sodium iodide.

Alternatively, the dealkylation reaction is carried out in a polar protic solvent such as water or ethanol in the presence of a strong acid such as hydrochloric acid at a temperature of about 0 ° C. to 100 ° C. for about 1 to 24 hours and is of the formula (VI ).

The starting compounds of formula (V) and formula (VII) are described in US patent application Ser. No. 08 / 237,081, Fang.
et al., Journal of Organic Chemistry, 59 (21), 6142.
−6153 (1994), PCT / US95 / 05425, and PCT / US95 / 054
27.

A compound of formula (III) can be oxidized to give a compound of formula (I).

The oxidation reaction is carried out in a suitable solvent such as methylene chloride,
About 0.1-
After about 1 hour, the compound of formula (I) can be obtained.
Other variations on these conditions are found in the literature on activated sulfur-based oxidants, such as Mancuso and
Swern, Synthesis, 165-185 (1981) and March, J., Advanced Organic Chemistry, 3rd Edition, J.
ohn Wiley & Sons, New York (1985), 1057-106
It will become clear from pages 0, 1081 to 1082.

Therefore, the compounds of formula (V) and (VI)
The progress to the compound of formula (I) through the intermediate compounds of V), (II), and (III) is schematically represented by the following process chart.

Another embodiment of the present invention is the formula (II), (III), (I
V) and (VI) are novel compounds.

Compounds of formula (II), (III), (IV), (V), (VI) and (VII) include camptothecin and camptothecin analogs such as compounds of formula (I), and Glaxo In
Intermediate in the manufacture of what is described in European Patent Application No. 0,540,099, A1 filed by C. and published on May 5, 1993 and whose contents are disclosed herein as part of its disclosure. It is useful as a body.

A typical preparation of camptothecin derivatives of formula (I) using intermediate compounds of formulas (II), (III), (IV), (V), (VI) and (VII) is exemplified herein. .

Examples The following examples illustrate various aspects of the invention and should not be construed as limiting the invention. Symbols, conventions, and terms not specifically defined below refer to modern chemical literature, such as the Journal of the American
It is consistent with that used by the Chemical Society.

In the examples below, "mg" means milligrams, "M" means moles, "mL" means milliliters, "mmol" means millimoles, "L" means liters. , "Mol" means moles, "g" means grams, "TLC" means thin layer chromatography,
"HPLC" means high pressure liquid chromatography,
"m" means millimole, "mp" means melting point, "Mh
“Z” means megahertz, “ ¹ H-NMR” means proton nuclear magnetic resonance, “Hz” means hertz, “h” means time, and “n” means positive.

Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. All reactions involving compounds sensitive to oxygen or moisture were performed under a dry N ₂ atmosphere. All reactions and chromatographic fractions were analyzed by thin layer chromatography on silica gel plates visualized by UV and I ₂ staining.

Example 1 4-Ethyl-1H-pyrano [3,4-c] pyridin-8-one (compound of formula (VI) wherein R ₅ is hydrogen and R ₆ is methyl) 250 mL single neck round bottom In a flask, U.S. Patent Application Serial No. 08 / 237,081, Fang et al., Journal of Org.
anic Chemistry, 59 (21) 21,6142-6143 (1994), PCT /
4-Ethyl-8-methoxy-1H-prepared by the method described in US95 / 05425 and PCT / US95 / 05427.
Pyrano [3,4-c] pyridine (10 g, 52.4 mmol), acetonitrile (100 mL), and sodium iodide (11.8 g,
79 mmol). The mixture is stirred at ambient temperature for about 20 minutes. To this mixture was added trimethylsilyl chloride (10
ml, 79 mmol) is immediately added, a white precipitate is formed. The resulting mixture is heated at reflux temperature for about 2 hours.
The reaction is cooled to ambient temperature. In the cooled reaction mixture,
Add 50 mL of sodium bicarbonate solution. The mixture is stirred at ambient temperature for 1 hour. The precipitate is collected by filtration on a Buchner funnel. The recovered solid is vacuum dried at 25-38 ° C. for about 12 hours, and the 4-ethyl-1H-pyrano [3,4-c] pyridin-8-one obtained first is obtained as a light tan crystalline solid. Obtained. The filtrate was concentrated in vacuo and the resulting residue was recrystallized from acetonitrile / methanol to give additional 4-ethyl-1H-pyrano [3,4-c] pyridin-8-one as a light tan crystalline solid. . Characterization data: mp 169
~ 171 ° C. ¹ HNMR (CDCl ₃ , 300MHz): δ1.11 (t, J = 7.4H
z, 3H), 2.27 (q, J = 7.4Hz, 2H), 5.04 (s, 2H), 6.17 (d,
J = 6.8Hz, 1H), 6.59 (s, 1H), 7.32 (d, J = 6.8Hz, 1H), 1
3.16 (bs, 1H).

Example 2 4-Ethyl-7- [7-iodo-9-[(4-methyl-
Piperazinyl) methyl] -2,3-dihydro- [1,4] dioxino [2,3-g] quinolin-8-ylmethyl] -1H-
Pyrano [3,4-c] pyridin-8-one (R ₂ is hydrogen, R ₃ and R ₄ together are ethylenedioxy, R ₅ is hydrogen, R ₆ is methyl , A compound of formula (IV) wherein X is iodo) 4-ethyl 1H-pyrano [3,4-c] pyridin-8-one (200 mg, 1.13 mmol), U.S. Patent Application Serial No. 08/23
7,081 Specification, Fang et al., Journal of Organic Chem
istry, 59 (21), 6142-6143 (1994), PCT / US95 / 05425
And [7-iodo-9-[(4-methyl-piperazinyl) methyl] -2,3-dihydro- [1,4] dioxino prepared by the method described in PCT / US95 / 05427. [2,3-g] quinolin-8-yl] -methanol (514m
g, 1.13 mmol) in 4.5 mL of dichloromethane, triphenylphosphine (326 mg, 1.24 mmol) is added. After stirring at ambient temperature for 3 minutes, the mixture was cooled to 0 ° C. and diethyl azodicarboxylate (0.20 mL, 1.24
mmol) is added dropwise. Warm the brown solution to ambient temperature,
Stir for 14 hours. The solvent is distilled off under reduced pressure and the resulting residue is chromatographed on silica gel. Elute with 5-10% methanol / dichloromethane to give 4-ethyl-7.
-[7-Iodo-9-[(4-methyl-piperazinyl)
Methyl] -2,3-dihydro- [1,4] dioxino [2,3-
g] quinolin-8-ylmethyl] -1H-pyrano [3,4-
c] Pyridin-8-one is obtained as a yellow solid product.
Characterization data: ¹ HNMR (200MHz, CDCl ₃ ): δ1.03 (t, J
= 7.4Hz, 3H), 2.18 (s, 3H), 2.25 (q, J = 7.4Hz, 2H), 2.
45 (br.s, 4H), 3.80 (s, 2H), 4.39 (s, 4H), 5.18 (s, 2
H), 5.45 (s, 2H), 5.94 (d, J = 6.8Hz, 1H), 6.60 (s, 1)
H), 6.80 (d, J = 6.8Hz, 1H), 7.52 (s, 1H), 7.67 (s, 1
H).

Example 3 11H-1,4-dioxino [2,3-g] pyrano [3 ′, 4 ′: 6,
7] Indolizino [1,2-b] quinolin-12 (14H) -one, 8-ethyl-2,3-dihydro-15-[(4-methyl-
1-piperazinyl) methyl] (R ₁ is 4-methylpiperazinyl-methyl, R ₂ is hydrogen, R ₃ and R ₄ together are ethylenedioxy, R ₅ is hydrogen ,
R ₆ is methyl, the compound of formula (II)) 4- ethyl-7 [7-iodo-9 - [(4-methyl - piperazinyl) methyl] -2,3-dihydro - [l, 4] dioxy [2,3-g] quinolin-8-ylmethyl] -1H-
Pyrano [3,4-c] pyridin-8-one (50.0 mg, 0.081
3 mmol) dissolved in 4 mL of acetonitrile, palladium (II) acetate (0.90 mg, 0.0040 mmol), anhydrous potassium carbonate powder (22.4 mg, 0.163 mmol), and triphenylphosphine (10.6 mg, 0.0406 mmol) were added to the surrounding environment. Add continuously at temperature. The mixture is brought to reflux temperature and stirred for 17 hours. The solvent is distilled off under reduced pressure and the resulting residue is chromatographed on silica gel. Elute with 10% methanol / chloroform to give 11H-1,4-dioxino [2,3-g].
Pyrano [3 ', 4': 6,7] indolidino [1,2-b] quinolin-12 (14H) -one, 8-ethyl-2,3-dihydro-15
-[(4-Methyl-1-piperazinyl) methyl] is obtained as a yellow solid product. Characterization data: mp 223--22
5 ° C. ¹ HNMR (300MHz, CDCl ₃ ): δ1.22 (t, J = 7.4Hz, 3
H), 2.29 (s, 3H), 2.45 (q, J = 7.4Hz, 2H), 2.57 (br.s,
4H), 3.94 (s, 2H), 4.44 (s, 4H), 5.20 (s, 2H), 4.83
(S, 1H), 5.29 (s, 2H), 6.67 (s, 2H), 7.14 (s, 1H), 7.
65 (s, 1H), 7.75 (s, 1H).

Example 4 11H-1,4-dioxino [2,3-g] pyrano [3 ′, 4 ′: 6,
7] Indolizino [1,2-b] quinoline-12 (8H, 14H)-
On, 8-ethyl-2,3-dihydro-8,9-dihydroxy-
15-[(4-methyl-1-piperazinyl) methyl]-
(9R-cis) (R ₁ is 4-methylpiperazinyl-methyl, R ₂ is hydrogen, R ₃ and R ₄ together are ethylenedioxy, R ₅ is hydrogen, A compound of formula (III) wherein R ₆ is methyl) The chiral ligand hydroquinidine 1,4 available from Aldrich Chemical Company, Milwaukee, Wyoming
-AD containing phthalazine diyl diether-Mix-β
(1.26 g) dissolved in 4 mL of water-tert-butyl alcohol (1: 1), methanesulfonamide (24 mg, 0.260 mmo
l) is added. After cooling the brown mixture to 0 ° C., 11H-1,
4-Dioxino [2,3-g] pyrano [3 ', 4': 6,7] indolidino [1,2-b] quinolin-12 (14H) -one, 8-ethyl-2,3-dihydro-15 -[(4-Methyl-1-piperazinyl) methyl] (126 mg, 0.260 mmol) is added. The mixture is warmed to ambient temperature and stirred vigorously for 36 hours. The mixture is diluted with 8 mL of water and quenched with 750 mg of sodium sulfite. After stirring for a further 20 minutes, the mixture was diluted with 5 mL of dichloromethane and filtered to give a solid product, which was dried under high vacuum, 11H-1,4-dioxino [2,3-g].
Pyrano [3 ', 4': 6,7] indolidino [1,2-b] quinolin-12 (8H, 14H) -one, 8-ethyl-2,3-dihydro-8,9-dihydroxy-15- [ (4-Methyl-1-piperazinyl) methyl]-(9R-cis) is obtained as a pale yellow solid product. ¹ HNMR shows alkoxy with a diastereomeric ratio of 83:17. Presumably the two diastereomers are epimeric at the hemiacetal carbon. Specific determination data (main epimer): mp 255-260 ℃,
With decomposition. ¹ HNMR (300 MHz, DMSO-d6): δ 0.97 (t, J
= 7.4Hz, 3H), 1.74 (t, J = 7.4Hz, 2H), 2.06 (s, 3H), 2.
29 (br.s, 4H), 3.89 (s, 2H), 4.39 (s, 4H), 4.51 (ABq,
J _AB = 39Hz, Δν = 82Hz, 2H), 4.83 (s, 1H), 4.95 (s, 1)
H), 5.26 (s, 2H), 7.23 (s, 1H), 7.54 (s, 1H), 7.70
(S, 1H).

In order to evaluate the enantiomeric selectivity of the above step, the above main diastereomers were separately (S)
-And (R) -O-methyl mandelate.
The above solid product (10 mg, 0.019 mmol), (S) -O-methylmandelic acid (6.4 mg, 0.038 mmol), 1,3-dicyclohexylcarbodiimide (7.9 mg, 0.038 mmol), and a catalytic amount of N, N- A mixture of dimethylaminopyridine in 2 mL dichloromethane is stirred for 2 hours at ambient temperature. The resulting white suspension is filtered through a short pad of Celite® and washed with 2 mL dichloromethane. The combined filtrate and washings are concentrated under reduced pressure to give a crude product as a solid product. Analysis of the entire ¹ H NMR spectrum (300 MHz, CDCl ₃ ) shows a diastereomeric ratio of 93: 7. This corresponds to an enantiomeric purity of 86% for the main product pentacyclic alcohol. The same ratio is obtained when preparing (R) -mandelate from the main alcohol. The signals for (S)-and (R) -O-methyl mandelate are complementary to each other. In each case, a sharp signal for the proton at the anomeric center is used for the analysis.

Example 5 11H-1,4-dioxino [2,3-g] pyrano [3 ′, 4 ′: 6,
7] Indolizino [1,2-b] quinoline-9,12 (8H-14
H) -dione, 8-ethyl-2,3-dihydro-8-hydroxy-15-[(4-methyl-1-piperazinyl) methyl]
-(S) (R ₁ is 4-methylpiperazinyl-methyl, R ₂ is hydrogen, R ₃ and R ₄ together are ethylenedioxy, R ₅ is hydrogen, R A compound of formula (I) in which ₆ is methyl) Oxalyl chloride (0.14 mL, 1.5 mmol) dissolved in 8 mL of dichloromethane was cooled to -78 ° C, and then dimethyl sulfoxide (0.22 mL, 3.1 mmol) was added dropwise. To do. After stirring the mixture for 2 minutes, 11H-1,4-dioxino [2,3-
g] pyrano [3 ', 4': 6,7] indolizino [1,2-b]
Quinoline-12 (8H, 14H) -one, 8-ethyl-2,3-dihydro-8,9-dihydroxy-15-[(4-methyl-1-
Piperazinyl) methyl]-(9R-cis) (40mg, 0.077m
mol) to dimethylsulfoxide (2 mL). -78 ° C
After stirring at room temperature for 15 minutes, add triethylamine (0.85
(mL, 6.2 mmol) is added dropwise for treatment. Remove the cooling tank,
Stirring is continued for 10 minutes. After quenching the reaction with 10 mL of water, the layers are separated and the aqueous layer is extracted three times with chloroform. The combined organic layers are washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The brown residue formed is chromatographed on silica gel.
Elution with 10% methanol / chloroform gave 11H-1,4-dioxino [2,3-g] pyrano [3 ', 4': 6,7] indolidino [1,2-b] quinoline-as a yellow solid product.
9,12 (8H, 14H) -dione, 8-ethyl-2,3-dihydro-
26 mg of 8-hydroxy-15-[(4-methyl-1-piperazinyl) methyl]-(S) (65% yield) are obtained. Characterization data: ¹ HNMR (300MHz, CDCl ₃ ): δ1.06 (t, J =
7.4Hz, 3H), 1.91 (m, 2H), 2.31 (s, 3H), 2.59 (br.s, 4
H), 3.80 (br.s, 1H), 3.97) s, 2H), 4.46 (s, 4H), 5.32
(S, 2H), 5.55 (ABq, J _AB = 8.4Hz, Δν = 90Hz, 2H), 7.60
(S, 1H), 7.66 (s, 1H), 7.72 (s, 1H).

─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Shipping, EXCIE, North Carolina, USA, Research, Triangle, Park, Five, Moore, Drive, Glaxo, Wellcome, Incorporated (56) References -139188 (JP, A) Tokumei Hyo 6-502642 (JP, A) International Publication 93/016698 (WO, A1) J. Med. Chem. , (1989), 32, p715-720 (58) Fields investigated (Int.Cl. ⁷ , DB name) C07D 491/22 CA (STN) REGISTRY (STN)

Claims (15)

(57) [Claims] 1. A compound of formula (II), under basic conditions,
A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which comprises dihydroxylating and oxidizing the compound of formula (III) formed. [In the above formula, R ₁ and R ₂ may be the same or different and are independently hydrogen, (C _1-8 ) alkyl, (C _3-7 ) cycloalkyl, (C _3-7 ) cyclo. Alkyl (C _1-8 )
Alkyl, lower alkenyl, hydroxy (C _{1 to 8)} alkyl or alkoxyalkyl at either, or a _{(-CH 2 NR 7 R 8)} , where i) R ₇ and R ₈ be the same or different Well, independently, hydrogen, (C _1-8 ) alkyl,
_{(C 3 to 7) cycloalkyl, (C 3 to 7)} cycloalkyl _{(C 1 to 8)} alkyl, lower alkenyl, hydroxy _{(C 1 to 8)} alkyl or lower alkoxy, (C
_1-8 ) alkyl, or ii) R ₇ is hydrogen, (C _1-8 ) alkyl,
_{(C 3 to 7) cycloalkyl, (C 3 to 7)} cycloalkyl _{(C 1 to 8)} alkyl, lower alkenyl, hydroxy _{(C 1 to 8)} alkyl or lower alkoxy, (C
_1-8 ) alkyl, and R ₈ is —COR ₉ (wherein R ₉ is hydrogen, (C _1-8 ) alkyl, perhalo (C _{8
1-8) alkyl, (C 3 to 7)} cycloalkyl, (C
_3-7 ) cycloalkyl ( _C1-8 ) alkyl, lower alkenyl, hydroxy ( _C1-8 ) alkyl, lower alkoxy, lower alkoxy ( _C1-8 ) alkyl)
Or iii) R ₇ is hydrogen or (C _1-8 ) alkyl and R ₈ is diphenyl-methyl or — (C
H ₂ ) _t Ar (where t is 0-5, Ar is optionally hydroxy, methyl, halogen,
And phenyl, furyl, pyridyl, N-methylpyrrolyl, imidazolyl) optionally substituted by one or more substituents selected from amino), or iv) R ₇ and R ₈ are attached nitrogen Together with
Form a saturated 3-7 atom heterocyclic group of formula (IA): {In the above formula, Y is O, S, SO, SO ₂ , CH ₂ , or NR ₁₀ , where R ₁₀ is hydrogen, (C _1-8 ) alkyl, perhalo (C _1-8 ) alkyl, Is aryl,
(C _1-8 ) alkyl, lower alkoxy, halogen, nitro, amino, (C _1-8 ) alkylamino, perhalo- (C _1-8 ) alkyl, hydroxy (C _1-8 ) alkyl, lower alkoxy (C _{1 ~ 8} ) an aryl substituted with one or more substituents selected from an alkyl group, or -COR ₁₁ (wherein R ₁₁ is hydrogen, (C _1-8 ) alkyl, perhalo (C
_1-8 ) alkyl, lower alkoxy, aryl, or (C _1-8 ) alkyl, perhalo (C _1-8 ) alkyl, hydroxy (C _1-8 ) alkyl, lower alkoxy (C _1-8 ) alkyl group Is an aryl substituted with one or more substituents selected from the following), R ₃ and R ₄ are independently hydrogen, (C _1-8 ) alkyl,
Selected from (C _3-7 ) cycloalkyl, (C _3-7 ) cycloalkyl (C _1-8 ) alkyl, lower alkenyl, hydroxy (C _1-8 ) alkyl, or alkoxyalkyl, or R ₃ and Do R ₄ together form a saturated 5 or 6 atom heterocyclic group of formula (IB): (In the above formula, n is an integer 1 or 2), or R ₃ is —OCONR ₁₂ R ₁₃ (wherein R ₁₂ and R ₁₃ may be the same or different,
Independently selected from hydrogen, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, or a substituted or unsubstituted carbocyclic or heterocyclic group, or R ₁₂ and R ₁₃ are Combined with the nitrogen atom to which they are attached, --O--, --S--, and / or --N--R
₁₄ (wherein R ₁₄ forms a heterocycle in which hydrogen may be inserted, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, or a substituted or unsubstituted phenyl group). , R ₅ is hydrogen or alkyl, and R ₆ is hydrogen or alkyl]. 2. A compound of formula (II) is prepared by the intramolecular Heck reaction cyclization of a compound of formula (IV) below under basic conditions in the presence of a palladium catalyst. Described method: [Wherein R _{1 to} R ₆ are as defined in claim 1 and X is triflate or halo]. 3. A compound of formula (IV) in the presence of a trialkyl- or triarylphosphine in an aprotic solvent or in a polar aprotic solvent under basic conditions: The process according to claim 2, which is prepared by condensing a compound of formula (V) with a compound of formula (VI): [Wherein R _{1 to} R ₆ are as defined in claim 1, X is triflate or halo, and Z is halo or OR ₁₅ , wherein R ₁₅ is hydrogen, triflate. , Mesylate or tosylate]. 4. The process according to claim 3, wherein the compound of formula (VI) is obtained by dealkylating a compound of formula (VII) below in a polar aprotic solvent: [Wherein R ₅ and R ₆ are as defined in claim 1 and R ₁₆ is alkyl]. 5. A process for preparing a compound of formula (I) which comprises oxidizing a compound of formula (III) below under basic conditions: [Wherein R _{1 to} R ₆ are as defined in claim 1]. 6. R ₁ is 4-methylpiperazinyl-methyl, R ₂ is hydrogen, R ₃ and R ₄ together are ethylenedioxy, R ₅ is hydrogen, and , R ₆ is methyl. _6. The method according to claim 1, wherein R ₆ is methyl. 7. The compound of formula (II) is 11H-1,4-dioxino [2,3-g] pyrano [3 ', 4': 6,7] indolidino [1,2-b] quinoline-12. (14H) -one, 8-ethyl-2,
The method of claim 1, which is 3-dihydro-15-[(4-methyl-1-piperazinyl) methyl]. 8. The compound of formula (III) is 11H-1,4-dioxino [2,3-g] pyrano [3 ', 4': 6,7] indolidino [1,2-b] quinoline-12. (8H, 14H) -one, 8-ethyl-2,3-dihydro-8,9-dihydroxy-15-[(4-methyl-1-piperazinyl) methyl]-(9R-cis). Or the method according to 5. 9. A compound of formula (II), (IV), or (VI) or a pharmaceutically acceptable salt thereof: [In the above formula, R ₁ and R ₂ may be the same or different and are independently hydrogen, (C _1-8 ) alkyl, (C _3-7 ) cycloalkyl, (C _3-7 ) cyclo. Alkyl (C _1-8 )
Alkyl, lower alkenyl, hydroxy (C _{1 to 8)} alkyl or alkoxyalkyl at either, or a _{(-CH 2 NR 7 R 8)} , where i) R ₇ and R ₈ be the same or different Well, independently, hydrogen, (C _1-8 ) alkyl,
_{(C 3 to 7) cycloalkyl, (C 3 to 7)} cycloalkyl _{(C 1 to 8)} alkyl, lower alkenyl, hydroxy _{(C 1 to 8)} alkyl or lower alkoxy, (C
_1-8 ) alkyl, or ii) R ₇ is hydrogen, (C _1-8 ) alkyl,
_{(C 3 to 7) cycloalkyl, (C 3 to 7)} cycloalkyl _{(C 1 to 8)} alkyl, lower alkenyl, hydroxy _{(C 1 to 8)} alkyl or lower alkoxy, (C
_1-8 ) alkyl, and R ₈ is —COR ₉ (wherein R ₉ is hydrogen, (C _1-8 ) alkyl, perhalo (C _{8
1-8) alkyl, (C 3 to 7)} cycloalkyl, (C
_3-7 ) cycloalkyl ( _C1-8 ) alkyl, lower alkenyl, hydroxy ( _C1-8 ) alkyl, lower alkoxy, lower alkoxy ( _C1-8 ) alkyl)
Or iii) R ₇ is hydrogen or (C _1-8 ) alkyl and R ₈ is diphenyl-methyl or — (C
H ₂ ) _t Ar (where t is 0-5, Ar is optionally hydroxy, methyl, halogen,
And phenyl, furyl, pyridyl, N-methylpyrrolyl, imidazolyl) optionally substituted by one or more substituents selected from amino), or iv) R ₇ and R ₈ are attached nitrogen Together with
Forming a saturated 3-7 atom heterocyclic group of formula (IA) {In the above formula, Y is O, S, SO, SO ₂ , CH ₂ , or NR ₁₀ , where R ₁₀ is hydrogen, (C _1-8 ) alkyl, perhalo (C _1-8 ) alkyl, Is aryl,
(C _1-8 ) alkyl, lower alkoxy, halogen, nitro, amino, (C _1-8 ) alkylamino, perhalo- (C _1-8 ) alkyl, hydroxy (C _1-8 ) alkyl, lower alkoxy (C _{1 ~ 8} ) an aryl substituted with one or more substituents selected from an alkyl group, or -COR ₁₁ (wherein R ₁₁ is hydrogen, (C _1-8 ) alkyl, perhalo (C
_1-8 ) alkyl, lower alkoxy, aryl, or (C _1-8 ) alkyl, perhalo (C _1-8 ) alkyl, hydroxy (C _1-8 ) alkyl, lower alkoxy (C _1-8 ) alkyl group Is an aryl substituted with one or more substituents selected from the following), R ₃ and R ₄ are independently hydrogen, (C _1-8 ) alkyl,
Selected from (C _3-7 ) cycloalkyl, (C _3-7 ) cycloalkyl (C _1-8 ) alkyl, lower alkenyl, hydroxy (C _1-8 ) alkyl, or alkoxyalkyl, or R ₃ and Do R ₄ together form a saturated 5 or 6 atom heterocyclic group of formula (IB): (In the above formula, n is an integer 1 or 2), or R ₃ is —OCONR ₁₂ R ₁₃ (wherein R ₁₂ and R ₁₃ may be the same or different,
Independently selected from hydrogen, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, or a substituted or unsubstituted carbocyclic or heterocyclic group, or R ₁₂ and R ₁₃ are Combined with the nitrogen atom to which they are attached, --O--, --S--, and / or --N--R
₁₄ (wherein R ₁₄ forms hydrogen, a heterocyclic ring in which a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, or a substituted or unsubstituted phenyl group) may be inserted. , R ₅ is hydrogen or alkyl, and R ₆ is hydrogen or alkyl]. 10. The compound according to claim 9, wherein R ₁ is — (CH ₂ NR ₇ R ₈ ), R ₂ is hydrogen, (C _1-8 ) alkyl, (C _3-7 ). ) _{cycloalkyl, (C 3 to 7)} cycloalkyl _{(C 1 to 8)}
Alkyl, lower alkenyl, hydroxy _{(C 1 to 8)} alkyl, alkoxyalkyl, _{or, (- CH 2 NR 7 R} 8)
I) R ₇ and R ₈ may be the same or different and are independently hydrogen, (C _1-8 ) alkyl,
_{(C 3 to 7) cycloalkyl, (C 3 to 7)} cycloalkyl _{(C 1 to 8)} alkyl, lower alkenyl, hydroxy _{(C 1 to 8)} alkyl or lower alkoxy, (C
_1-8 ) alkyl, or ii) R ₇ is hydrogen, (C _1-8 ) alkyl,
_{(C 3 to 7) cycloalkyl, (C 3 to 7)} cycloalkyl _{(C 1 to 8)} alkyl, lower alkenyl, hydroxy _{(C 1 to 8)} alkyl or lower alkoxy, (C
_1-8 ) alkyl, and R ₈ is —COR ₉ (wherein R ₉ is hydrogen, (C _1-8 ) alkyl, perhalo (C _{8
1-8) alkyl, (C 3 to 7)} cycloalkyl, (C
_3-7 ) cycloalkyl ( _C1-8 ) alkyl, lower alkenyl, hydroxy ( _C1-8 ) alkyl, lower alkoxy, lower alkoxy ( _C1-8 ) alkyl)
Or iii) R ₇ is hydrogen or (C _1-8 ) alkyl and R ₈ is diphenyl-methyl or — (C
H ₂ ) _t Ar (where t is 0-5, Ar is optionally hydroxy, methyl, halogen,
And phenyl, furyl, pyridyl, N-methylpyrrolyl, imidazolyl) substituted by one or more substituents selected from amino) or iv) R ₇ and R ₈ together with the nitrogen to which they are attached. Become,
Form a saturated 3-7 atom heterocyclic group of formula (IA): {In the above formula, Y is O, S, SO, SO ₂ , CH ₂ , or NR ₁₀ , where R ₁₀ is hydrogen, (C _1-8 ) alkyl, perhalo (C _1-8 ) alkyl, Is aryl,
(C _1-8 ) alkyl, lower alkoxy, halogen, nitro, amino, (C _1-8 ) alkylamino, perhalo- (C _1-8 ) alkyl, hydroxy (C _1-8 ) alkyl, lower alkoxy (C _{1 ~ 8} ) an aryl substituted with one or more substituents selected from an alkyl group, or -COR ₁₁ (wherein R ₁₁ is hydrogen, (C _1-8 ) alkyl, perhalo (C
_1-8 ) alkyl, lower alkoxy, aryl, or (C _1-8 ) alkyl, perhalo (C _1-8 ) alkyl, hydroxy (C _1-8 ) alkyl, lower alkoxy (C _1-8 ) alkyl group Is an aryl substituted with one or more substituents selected from 11. A compound according to claim 10, wherein R ₇ and R ₈ together with the nitrogen to which they are attached are saturated 3 to 7 atom heterocycles of formula (IA) A compound forming a cyclic group: {In the above formula, Y is O, S, SO, SO ₂ , CH ₂ , or NR ₁₀ , where R ₁₀ is hydrogen, (C _1-8 ) alkyl, perhalo (C _1-8 ) alkyl, Is aryl,
(C _1-8 ) alkyl, lower alkoxy, halogen, nitro, amino, (C _1-8 ) alkylamino, perhalo- (C _1-8 ) alkyl, hydroxy (C _1-8 ) alkyl, lower alkoxy (C _{1 ~ 8} ) an aryl substituted with one or more substituents selected from an alkyl group, or -COR ₁₁ (wherein R ₁₁ is hydrogen, (C _1-8 ) alkyl, perhalo (C
_1-8 ) alkyl, lower alkoxy, aryl, or (C _1-8 ) alkyl, perhalo (C _1-8 ) alkyl, hydroxy (C _1-8 ) alkyl, lower alkoxy (C _1-8 ) alkyl group Is an aryl substituted with one or more substituents selected from 12. A compound of formula (III) or a pharmaceutically acceptable salt thereof: [In the above formulas, R ₁ is _{(-CH 2 NR 7 R 8)} , R 2 is _{hydrogen, (C 1 to 8) alkyl, (C 3 to 7) cycloalkyl, (C 3 to 7)} cycloalkyl Alkyl (C _1-8 )
Alkyl, lower alkenyl, hydroxy _{(C 1 to 8)} alkyl, alkoxyalkyl, _{or, (- CH 2 NR 7 R} 8)
And R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ are as defined in claim 9]. 13. R ₁ is 4-methylpiperazinyl-methyl, R ₂ is hydrogen, R ₃ and R ₄ together are ethylenedioxy, R ₅ is hydrogen, and , R ₆ is methyl, compound according to claim 9 or 12. 14. A compound according to claim 9 selected from the group consisting of: 4-ethyl-1H-pyrano [3,4-c] pyridin-8-one, 4-ethyl-7- [7. -Iodo-9-[(4-methyl-
Piperazinyl) methyl] -2,3-dihydro- [1,4] dioxino [2,3-g] quinolin-8-ylmethyl-1H-pyrano [3,4-c] pyridin-8-one, and 11H-1. , 4-Dioxino [2,3-g] pyrano (3 ', 4': 6,
7] Indolizino [1,2-b] quinolin-12 (14H) -one, 8-ethyl-2,3-dihydro-15-[(4-methyl-
1-piperazinyl) methyl]. 15. 11H-1,4-dioxino [2,3-g] pyrano [3 ', 4': 6,7] indolidino [1,2-b] quinolin-12 (8H, 14H) -one, 8-ethyl-2,3-dihydro-8,9
The compound of claim 12, which is -dihydroxy-15-[(4-methyl-1-piperazinyl) methyl]-(9R-cis).